Local and Hormonal Mediators

Question 1

What are local mediators? Give examples.

Answer 1

Quite often, they usually only act locally because they are labile or rapidly metabolised/’diluted’ beyond their biologically active range close to their site of release.

They have many modulatory functions including smooth muscle tone/length, glandulat secretion, permeability (vascular & airway) and sensory nerves (pain & itch).

There are many examples including histamine (small amine), bradykinin (peptide) and Nitrix oxide (NO).

Question 2

Give the general features of Histamine

Answer 2

Largely store in and released from Mast Cells (tissues-particularly mucosal surfaces/skin) and Basophils (blood). The are enterochromaffin-like cells (GIT) that regulate stomach acid secretion. There are also periperal and central histaminergic neurones.

Stimuli that induces histamine release include:

- antigen via IgE
- complement fragments C3a/C5
- neuropeptides
- cytokines & chemokines
- bacterial components (PAMPs)
- physical trauma (DAMPs)

Histamine mediates its activities through interacting with 4 receptors (H1, H2, H3, H4). There are selective agonists and antagonists that exist to all receptor classes which are all GPCRs.

Question 3

Explain the ‘triple response’ of histamine

Answer 3

Histamine can involve a triple response. This involves:

• Reddening: vasodilation at initiating site
• Wheal: increase in vascular permeability
• Flare: spreading response though sensory fibres

Question 4

What are H1 Receptor antagonists?

Answer 4

Antihistamines

Question 5

What are antihistamines used to treat?

Answer 5

These agents (mainly H1 blockers) are useful in treating:
- Hayfever (allergic rhinitis)
- atopic dermatitis (adjunct to glucocorticoids)
- urticaria
- analphylaxis & angiodema (adjunct to adrenaline)
- bites & stings
- Pruritus (H4 also)
- Motion sickness
BUT: Not effective in asthma

Question 6

What are the classes of antihistamines?

Answer 6

Competitive, reversible antagonists of H1 receptors fall into three classes/generations:

1) Sedative: (chlorpheniramine, promethazine)
- sedation may ne neutral/beneficial in treatment of allergic condition, but sufficient to interfere with lifestyle
2) Non-sedative: (terfenadine, astemizole)
- poor entry to CNS
- lack anti-muscarinic activity and GIT effects but can cause rare, sudden ventricular arrythmia (withdrawn)
3) Newer Non-sedative agaents: (cetirizine, loratidine)
- reduced risk of unwanted cardiac effects

Question 7

Explain H2 receptor antagonists.

Answer 7

These were revolutionary in the treatment of peptic ulcers as they were considered ‘blockbuster drugs’. Examples include cimetidine and ranitidine.

The improved understanding of the condition has led to alternative methods of treating peptic ulcers.

Question 8

Give an example of a regulatory protein/peptide.

Answer 8

• Can range in size from just a few amino acids to many hundred residues (ie bradykinin)

Question 9

What is bradykinin?

Answer 9

BK is an example of an autacoid that is a local peptide mediator in pain and inflammation. It is generated after plasma exudation during inflammation.

Question 10

How is bradykinin broken down?

Answer 10

By Kininase II which is otherwise commonly known as Angiotensin converting enzyme (ACE)

Question 11

What are the actions of bradykinin?

Answer 11

The actions of BK are:
Vascular:
- dilates arterioles & veules (released PGs/NO)
- increased vascular permeability
Neural:
- stimulates sensory nerve endings: pain
Other:
- contract uterus, airways & gut
- epithelial secretion in airways and gut

Question 12

What can antagonism of the BK receptors acheive?

Answer 12

Selective B2 receptor antagonist (icatibant) has a clinical use that is limited at present but may be effective in hereditary angioedema.

Question 13

Explain the actions of Ach in vascular smooth muscle reactivity.

Answer 13

There is a conundrum in vascular reactivity in so far as Acetylcholine acts as a vasodilator in vivo and a vasoconstrictor in vitro.

This is because in endothelium, Ach releases a relaxing factor that dilates the tissues and in vascular smooth muscle if it is at a high enough concentration then it can cause contraction.

Question 14

What is EDRF?

Answer 14

EDRF (endothelium-derived relaxant factor); exhaustive studies demonstrate that EDRF is nitric oxide (NO)

Question 15

What is the action of NO or EDRF?

Answer 15

Endothelium-derived VASOACTIVE factors include Prostacyclin (PGI2), EDRF, ERHF and Nitric oxide which relax muscles and Endothelin which contracts muscle.

Question 16

What are the three isoforms of NOS?

Answer 16

• three isoforms:
  
  • nNOS (nerves, epithelial cells)
  • iNOS (inducible- macrophages, smooth muscle)
  • eNOS (endothelial cells)

Question 17

Explain the action of NOS inhibitors?

Answer 17

L-arginine analogues: N-nitro-L-arginine methyl ester (L-NAME)
These produce vasoconstriction and hypertension as well as the basal release of NO which regulates vascular tone.

The physiological roe of NO is that is produces flow-dependent vasodilation. The NO release is in response to shear forces and has consequences for endothelial damage and dysfunction. It also inhibits platelet adhesion and aggregation as well as acting as a neurotransmitter.